PAINFUL PERIPHERAL NEUROPATHY AND ITS NONSURGICAL TREATMENT

INVITED REVIEW ABSTRACT: Treatment of neuropathic pain is the primary focus of management for many patients with painful peripheral neuropathy. Antidepressants and anticonvulsants are the two pharmacological classes most widely studied and represent first-line agents in the management of neuropathic pain. The number of pharmacological agents that have demonstrated effectiveness for neuropathic pain continues to expand. In the current review, we summarize data from randomized, controlled pharmacological trials in painful peripheral neuropathies. Although neuropathic pain management remains challenging because the response to therapy varies considerably between patients, and pain relief is rarely complete, a majority of patients can benefit from monotherapy using a well-chosen agent or polypharmacy that combines medications with different mechanisms of action. Muscle Nerve 30: 3 19, 2004 PAINFUL PERIPHERAL NEUROPATHY AND ITS NONSURGICAL TREATMENT GIL I. WOLFE, MD, and JAYA R. TRIVEDI, MD Department of Neurology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, Texas 75390-8897, USA Accepted 16 February 2004 Abbreviations: 5-HT, 5-hydroxytryptamine; ART, antiretroviral therapy; CI, confidence interval; CNS, central nervous system; FDA, Food & Drug Administration; GABA, -aminobutyric acid; HIV, human immunodeficiency virus; NMDA, N-methyl-D-aspartate; NNT, number needed to treat; SSRI, selective serotonin reuptake inhibitor; VAS, visual analogue Key words: anticonvulsants; antidepressants; neuropathic pain; peripheral neuropathy; treatment Correspondence to: G. I. Wolfe; e-mail: gil.wolfe@utsouthwestern.edu 2004 Wiley Periodicals, Inc. Published online 26 April 2004 in Wiley InterScience (www.interscience.wiley. com). DOI 10.1002/mus.20057 Neuropathic pain is conventionally defined as pain initiated or caused by injury or dysfunction of the nervous system. 58 The injury or dysfunction may involve peripheral or central nervous system structures. Neuropathic pain is common, estimated to affect 1.5% of the United States population. 12 When including disorders that are not categorized as conventional neuropathic pain states, the prevalence is even higher. 92 Poorly controlled neuropathic pain is associated with mood and sleep disturbance and an impaired ability to work and participate in social and recreational activities. 26 It is expected that neuropathic pain will be a growing burden on health care and society resources as the aged population increases worldwide. Peripheral nerve disorders are the major cause of neuropathic pain encountered by neurologists and other clinicians. 25 Neuropathic pain is a prominent feature of many generalized, symmetrical polyneuropathies. Even after extensive evaluation, a cause for the polyneuropathy may remain unknown in most patients, especially when small fibers are exclusively or predominantly involved. 45,69 In such settings, a diagnosis of idiopathic or cryptogenic sensory polyneuropathy is made. 35,36,99 Of identifiable etiologies, diabetes is the most common cause of painful polyneuropathy, but there are many other potential etiologies for painful polyneuropathies and mononeuropathies. 101 For simplicity, the current review at times uses the terms neuropathy and peripheral neuropathy (which have no specific implications) in place of polyneuropathy, which implies a generalized, symmetrical disorder of peripheral nerves. The frequency, intensity, and quality of neuropathic pain, though subject to individual variability, differ between etiologies. Postherpetic neuralgia is defined by a neuropathic pain experience, and 90% of patients with Fabry disease have pain 48 that classically is lancinating and lightning-like, aggravated by cold or exertion. Neuropathic pain is present in 65 80% of idiopathic polyneuropathies 100 and up to one third of diabetic patients 25 and patients with acquired immunodeficiency syndrome 82 but is uncommon in paraprotein-associated neuropathies. Although chronic therapy is required for many types of neuropathic pain, Guillain Barré syndrome and toxic neuropathies typically require only short-term intervention. SYMPTOMS AND SIGNS OF NEUROPATHIC PAIN The symptoms of neuropathic pain are often referred to as the positive symptoms of peripheral Treatment of Painful Neuropathy MUSCLE & NERVE July 2004 3

neuropathy. Negative sensory symptoms and signs of peripheral neuropathy refer to reports of numbness and the finding of reduced or absent sensation on sensory examination. Spontaneous (stimulusindependent) and stimulus-evoked pain, which can be distinguished by history and sensory examination, often coexist in individuals and are likely to represent different pathophysiological mechanisms. 104 Spontaneous pain may be constant or intermittent. It is common for patients to experience both persistent burning pain and superimposed episodes of shooting or lancinating discomfort. Paresthesias are abnormal spontaneous or stimulus-independent sensations, often described as tingling or compared to a limb that has fallen asleep. Descriptors of spontaneous painful sensation vary widely in patients and include burning, stabbing, stinging, squeezing, aching, cramping, shooting, and freezing. Pins and needles, broken glass, and vicelike sensations may be elicited by history. Stimulus-evoked pain is also common and is experienced in a variety of forms. Dysesthesia refers to an unpleasant abnormal sensation that can be spontaneous or evoked; allodynia, to pain following contact by a normally nonnoxious stimulus; and hyperalgesia, to exaggerated pain from a noxious stimulus. 58 Hyperpathia is a complex sensory experience characterized by an abnormally painful reaction to a stimulus, especially a repetitive stimulus, in a patient who initially perceives the stimulus as less intense, due to an increased threshold. A variety of positive symptoms often coexist in an individual. Given the lengthdependent pattern of many peripheral neuropathies, neuropathic pain symptoms tend to predominate in the distal limbs, typically involving the feet to a greater degree than the hands. 99 Sensory neuropathy appears to be the most common cause for the painful or burning-foot presentation. In a cohort of 117 patients presenting with painful, burning feet, 89% had objective evidence of peripheral neuropathy based on a variety of studies including electrophysiological testing and intraepidermal nerve fiber density on punch skin biopsy. 69 NEUROPATHIC PAIN MECHANISMS The pathophysiological basis of neuropathic pain is complex and not fully understood. Some background, however, is helpful in strategizing treatment approaches. Peripheral mechanisms include altered sensitivity and activation of C nociceptor terminals resulting in ectopic discharges in damaged or regenerating fibers, recruitment of silent nociceptors, and spontaneous discharges in more proximal segments of the sensory nerve, including the dorsal root ganglion. 64,104 Changes in expression and permeability of voltage-gated sodium channels appear to be common events in these peripheral alterations, 20 and several agents (tricyclic antidepressants, carbamazepine, topiramate, lamotrigine, mexiletine) have activity at these ion channels. Damaged peripheral nerve fibers express -adrenoreceptors and exhibit heightened sensitivity to sympathetic stimulation, raising the possibility of a sympathetically mediated component to neuropathic pain states. 5 Waves of increased peripheral nerve activity move centrally, producing central sensitization in secondand third-order neurons. It is the process of central sensitization that alters the way neurons respond to subsequent sensory input. 32,103 The alterations include the enlargement of peripheral receptive fields to stimuli, enhanced responses to suprathreshold inputs, and generation of action potentials by previously subthreshold inputs. Central sensitization appears to result from increased and prolonged release of excitatory amino acids such as glutamate and neuropeptides. 104 For instance, enhanced release of substance P as a result of prolonged activity along nociceptive pathways can potentiate activation of postsynaptic N-methyl-d-aspartate (NMDA) receptors. Subsequently, additional ion channels open, intracellular calcium concentrations build, and action potential generation is potentiated in central sensory pathways. 6 Neuropeptides may diffuse through the dorsal horn, sensitizing neurons that would otherwise be bystanders, producing the phenomenon of enlarged peripheral receptive fields, thus causing a perception of pain over a wider distribution and of greater intensity. Some of the newer agents used for neuropathic pain (gabapentin, lamotrigine, topiramate, tramadol, venlafaxine) are thought to inhibit central sensitization by blocking the activity of glutamate, excitatory neuropeptides, and presynaptic calcium channels and enhancing inhibitory pathways such as those mediated by -aminobutyric acid (GABA) and its receptors. A variety of pathophysiological processes may be at work in an individual patient, and the same mechanisms may not be present in all patients who share a specific neuropathic pain state. This pathophysiological variability likely accounts for some of the heterogeneity of patient responses to therapeutic interventions. 24 CLINICAL TRIALS AND DRUG INDICATIONS Most randomized, controlled pharmacological studies in neuropathic pain have evaluated antidepressants and anticonvulsants. Clinical trials of treatment 4 Treatment of Painful Neuropathy MUSCLE & NERVE July 2004

for neuropathic pain in peripheral neuropathy share a number of challenges and shortcomings. The response to placebo is considerable, typically observed in one third 3,33,51 and at times in more than one half of subjects. 10 Although statistically significant differences may be demonstrated between active treatment and placebo arms, the actual clinical benefit of a 1- or 2-point drop on a 10-point visual analogue (VAS) for pain intensity may be a point of debate. Although they provide objective data, neurophysiological measurements have not been helpful. 87 There is conflicting efficacy data for some agents. 14,40,47,76 Active treatment durations in studies are short, usually ranging from 6 weeks 21,33,51,78 to 8 weeks. 3,10 Although studies demonstrate a favorable pharmacological effect commencing in a matter of days to weeks, 87 long-term efficacy remains uncertain. Furthermore, the effect of medications on different aspects of neuropathic pain (e.g., steady versus episodic, spontaneous versus stimulus evoked) is rarely analyzed. 89 There are very few studies using combinations of agents. A study to determine whether combined therapy with an antidepressant and anticonvulsant is superior to either agent alone has not been performed. Another consideration for United States clinicians is that the use of the agents in neuropathic pain states related to polyneuropathy is off-label. Labeled neuropathic pain indications in the United States are limited to carbamazepine for trigeminal neuralgia and gabapentin and lidocaine patches for postherpetic neuralgia. Some countries permit more liberal indications that cover neuropathic pain in general, whereas others require labeling for only specific forms. 15 In some countries, including Japan, off-label use of medication is not permitted, influencing medication options. As a result, Japanese clinicians rarely prescribe tricyclic antidepressants for neuropathic pain. A variety of measures have been utilized in neuropathic pain studies. Visual analogue s or 10-point and 11-point s such as the Likert (0 no pain, 10 worst possible pain) are conventional primary measures. Patients record their pain levels in daily diaries, and mean values over a specified interval are compared with baseline values obtained prior to randomization. The short-form McGill pain questionnaire, 56 which consists of 15 pain descriptors (11 sensory [throbbing, shooting, stabbing, sharp] and four affective [tiring-exhausting, sickening, fearful, punishingcruel]) graded from 0 to 3, has served as either a primary or secondary. Although the instruments provide reliable and valid measurements of pain intensity and unpleasantness, they do not address other aspects of the neuropathic pain experience. 27 As a result, a variety of quality-of-life and daily activity measures have been introduced, especially in more recent trials. The Wisconsin Brief Pain Questionnaire a survey that includes 11-point rating s for worst pain, pain right now, and average pain but also assesses the effect of pain on mood, sleep, and daily activities has been used on occasion. 18 Other secondary measures provide global impressions of change from the standpoint of both study subject and clinician. Quality-of-life instruments employed in neuropathic pain studies include the General Health Self-Assessment form and the Short Form 36 Quality-of-Life Questionnaire. Galer and Jensen 27 recently developed and validated the Neuropathic Pain Scale, the first survey designed primarily for neuropathic pain. The includes items that address pain intensity, temporal patterns, and ratings for various descriptors of the neuropathic pain experience. The Neuropathic Pain Scale can generate distinct patterns for different neuropathic pain syndromes, a finding that has potential implications for underlying pain mechanisms and treatment. TRICYCLIC ANTIDEPRESSANTS Tricyclic antidepressants presumably exert their analgesic effect by modulating voltage-gated sodium channels and inhibiting the reuptake of the biogenic amines norepinephrine and serotonin. They are the agents most extensively studied for neuropathic pain, especially in diabetic neuropathy. 8,24 Randomized, controlled trials for the tricyclics in painful peripheral neuropathy are outlined in Table 1. Efficacy for the individual agents is roughly similar, 51,90 although tricyclics with mixed serotonergic and noradrenergic reuptake inhibition (e.g., amitriptyline, imipramine, and clomipramine) have been marginally more effective than those with relatively selective noradrenergic effects (desipramine, nortriptyline, and maprotiline). 96 Patients may preferentially respond to one tricyclic antidepressant over another, so that sequential therapeutic trials may be needed. 50 Tricyclics have been effective in relieving pain in both depressed and nondepressed patient subgroups, with an analgesic action that is independent of mood alteration and that becomes clinically evident as early as 1 to 2 weeks. 49,55 Tricyclics have been effective in both diabetic and nondiabetic forms of painful neuropathy. 96 The degree of analgesic re- Treatment of Painful Neuropathy MUSCLE & NERVE July 2004 5

Table 1. Randomized, placebo-controlled trials of tricyclic antidepressants.* Ref. no. Cause of neuropathy Drug Daily dose (mg) n Design 44 DM Imipramine 100 12 Crossover 5wk 30 DM Nortriptyline ( 60 18 Crossover fluphenazine) 30 days 49 DM Amitriptyline 90 (mean) 29 Crossover 6wk 87 DM Imipramine 200 (mean) 20 Crossover 2wk 88 DM Clomipramine 75 19 Crossover 2wk 88 DM Desipramine 200 19 Crossover 2wk 50 DM Desipramine 201 (mean) 20 Crossover 6wk 91 DM Imipramine 150 (mean) 18 Crossover 2wk 96 DM and Amitriptyline 75 33 Crossover non-dm 4wk 96 DM and Maprotiline 75 33 Crossover non-dm 4wk 80 HIV Amitriptyline 75 136 Parallel 14 wk 40 HIV Amitriptyline vs. 100 145 Parallel mexiletine 10 wk 85 Various Imipramine 150 32 Crossover 4wk Primary Result of primary on active drug (%) on placebo (%) Six-item P 0.10 58 0 VAS score P 0.01 89 6 Numeric global assessment P 0.0001 79 3 VAS score P 0.0002 89 15 Six-item observer Six-item observer Pain intensity score P 0.05 74 5 0.05 P 0.10 53 5 P 0.01 55 20 Six-item P 0.03 44 11 10-step verbal 10-step verbal Pain intensity score Pain intensity score 10-point rating s P 0.002 67 24 P 0.053 42 24 P 0.99 47 51 P 0.38 50 48 P 0.0005 48 7 Abbreviations: DM, diabetes mellitus; N/A, not available. *Main adverse events were mouth dryness (up to 90%), sedation (up to 66%), and dizziness (up to 28%). Placebo was infused with benztropine diazepam, to mimic tricyclic side effects. sponse has correlated directly with serum tricyclic levels in some studies 49,88 but not in others. 50,51,91,96 Tricyclics have demonstrated greater therapeutic effects than selective serotonin reuptake inhibitors such as paroxetine, but suboptimal plasma concentrations may be partly to blame for this observation. 87 The nontricyclic antidepressant mianserin, a drug that blocks 5-hydroxytryptamine (5-HT) receptors and that possesses only weak noradrenergic reuptake inhibition, was not effective in relieving painful diabetic neuropathy. 91 Of note, neither amitriptyline at doses up to 100 mg/day nor a standardized acupuncture regimen either alone or in combination was more effective than placebo in randomized trials of human immunodeficiency virus (HIV) related painful neuropathy (Table 1). 40,80 Possible explanations for the negative trials include mechanistic factors in HIV-related neuropathy that are more resistant to tricyclic actions, the modest doses used, and failure of amitriptyline to have a persistent benefit in longer duration studies. The clinical impression that antidepressants are more effective for burning pain whereas anticonvulsants are preferred for shooting, lancinating pain has not been verified in clinical trials; the benefit of tricyclics is not dependent on the quality of pain. 51,55 Shortcomings of studies include dropout rates of 30% or more in some trials, often the result of adverse events, 49,87 and treatment durations as short as 2 weeks (Table 1). Also, many of the earlier crossover trials did not employ washout periods between the various interventions. 44,50,87,88 As is true for most agents, the use of tricyclic antidepressants in neuropathic pain is off-label. Low doses (10 25 mg) can be given at bedtime and slowly increased by 10 to 25 mg every 1 to 2 weeks up to 100 150 mg as tolerated. Slower titration rates may be better tolerated by the elderly. Daily tricyclic doses between 75 and 150 mg are likely to fall within the effective range for most patients. 51 The main side effects of the tricyclics include dry mouth, sedation, urinary retention, cardiac arrhyth- 6 Treatment of Painful Neuropathy MUSCLE & NERVE July 2004

Ref. no. Cause of neuropathy Table 2. Randomized, placebo-controlled trials of other antidepressants.* Daily dose (mg) n Design Primary Drug 87 DM Paroxetine 40 20 Crossover 2wk 51 DM Fluoxetine 40 46 Crossover 6wk 86 DM Citalopram 40 15 Crossover 3wk 78 Various Bupropion 300 41 Crossover SR 6wk 85 Various Venlafaxine 225 32 Crossover 4wk Result of primary on active drug (%) on placebo (%) VAS score P 0.0121 50 15 Pain intensity score Six-item observer Wisconsin Brief Pain questionnaire 10-point rating s Abbreviations: DM, diabetes mellitus; N/A, not available. *Main adverse events were mouth dryness (up to 37%), fatigue (up to 28%), and insomnia (up to 20%). Placebo was infused with benztropine, to mimic side effects. P 0.34 48 41 P 0.02 N/A N/A P 0.001 73 10 P 0.004 27 7 mias, orthostatic hypotension, dizziness, constipation, and weight gain. 25,101 The secondary amines (nortriptyline, desipramine) tend to be less sedating and have less anticholinergic activity. Tricyclic antidepressants are contraindicated in patients with cardiac arrhythmias, congestive heart failure, recent myocardial infarction, drug sensitivity, narrow-angle glaucoma, and urinary retention from prostatic hypertrophy or other causes. Drug interactions may occur from concurrent use of central nervous system depressants or anticholinergic agents. The agents should be used with caution in elderly patients, who often are especially sensitive to adverse effects. SELECTIVE SEROTONIN REUPTAKE INHIBITORS Selective serotonin reuptake inhibitors (SSRIs) have been less effective than tricyclic antidepressants in controlled studies of neuropathic pain (Table 2). Although both imipramine and paroxetine demonstrated benefit compared with placebo in painful diabetic neuropathy, the tricyclic was significantly more efficacious than paroxetine on both an observer and self-rating. 87 Scores for dysesthesia, hypesthesia, and sleep disturbance did not improve on paroxetine. However, paroxetine was better tolerated by patients. Citalopram was of mild benefit in painful diabetic neuropathy. 86 No relation between drug level and analgesic effect was observed. In another trial, fluoxetine was no more effective than placebo in providing pain relief except in a subgroup of patients with depression. 51 Because fluoxetine has an active metabolite with a very long halflife, the study s crossover design may have clouded a distinction between the active drug and placebo. 90 Adverse events for the SSRIs tend to be mild and include somnolence or insomnia, asthenia, nausea, diarrhea, sweating, dry mouth, decreased libido, and impotence. Because neuropathic pain trials suggest that the rate of major side effects for SSRIs is half that observed for the tricyclics, 55 the SSRIs bear some clinical relevance despite lower efficacy. 86 The SSRIs may be particularly beneficial in depressed patients with neuropathic pain. ATYPICAL ANTIDEPRESSANTS Prominent adverse events and poor tolerability of tricyclic antidepressants have prompted investigation of atypical antidepressants with unique pharmacological profiles (Table 2). Bupropion is a second-generation nontricyclic antidepressant that specifically inhibits neuronal norepinephrine uptake. It is a weak inhibitor of dopamine reuptake. Unlike tricyclic agents, it does not have significant affinity for muscarinic, histaminergic, or -adrenergic receptors, and it is often better tolerated. 1 The sustained-release form of bupropion has been subjected to a double-blind randomized crossover trial in 41 patients with various forms of painful neuropathy. 78 Among the patients, 70% had either idiopathic, diabetic and paraprotein-related neuropathies, or lumbar radiculopathy. Pain relief was significant at week 2 and persisted through week 6 of the study (Table 2). A 30% reduction in pain scores relative to placebo was observed, similar to tricyclic studies. Quality-of-life measures also improved, and the drug was relatively well tolerated. Only two patients (5%) dropped out of the study because of side effects related to sustained-release bupropion. 78 Of Treatment of Painful Neuropathy MUSCLE & NERVE July 2004 7

Table 3. Randomized, placebo-controlled trials of gabapentin.* Ref. no. Cause of neuropathy Daily dose (mg) n Design 3 DM 900 3600 135 Parallel 8 weeks 31 DM 900 40 Crossover 6 weeks 67 GBS 15 mg/kg 18 Crossover 16 days 79 Various 2400 232 Parallel 8 weeks Primary 11-point Likert McGill Pain Questionnaire Numeric pain score Average daily pain score Result of primary on active drug (%) on placebo (%) P 0.001 59 33 P 0.03 43 23 P 0.001 N/A N/A P 0.048 N/A N/A Abbreviations: DM, diabetes mellitus; GBS, Guillain Barré syndrome; N/A not available. *Main adverse events were dizziness (up to 24%) and somnolence (up to 23%). the 11 patients enrolled in the study who had previously discontinued tricyclics because of side effects, only one was unable to tolerate buproprion. The main side effects of bupropion are dry mouth, headache, nausea, insomnia, and tremor. Bupropion is contraindicated in patients with a known seizure disorder, those taking a monoamine oxidase inhibitor, and those with known hypersensitivity to the medication. Buproprion should not be used in individuals with a current or prior diagnosis of bulimia or anorexia nervosa because of a higher incidence of seizures in this population. 102 Venlafaxine is an antidepressant that strongly inhibits the reuptake of both serotonin and norepinephrine but has minimal muscarinic and histaminergic activity compared with tricyclics. 37 In a preliminary report of a large study of 244 patients, venlafaxine extended-release was superior to placebo in nondepressed patients with painful diabetic neuropathy. 42 Effective doses were 150 225 mg/day. A double-blinded, placebo-controlled study showed significantly improved pain reduction, mood, and quality of life when venlafaxine was added to gabapentin in painful diabetic neuropathy. 81 Doses of up to 150 mg/day were used. Recently, venlafaxine was compared with imipramine in a randomized, double-blinded, placebo-controlled, three-way crossover study (Table 2). At the end of the 4-week treatment periods, both venlafaxine and imipramine were superior to placebo in reducing pain scores. 85 There was no statistical difference between venlafaxine and imipramine in efficacy. This is one of the few studies to compare responses in diabetic and nondiabetic subgroups. There was a trend for diabetic patients to experience greater pain relief than subjects with other forms of painful neuropathy, although this has not been the experience from other trials. 90 Side effects of venlafaxine include nausea, dizziness, somnolence, insomnia, sexual dysfunction, and dry mouth. Prior hypersensitivity and concomitant use of monoamine oxidase inhibitor are contraindications to using this drug. Tolerability of venlafaxine may not be superior to tricyclics, as side-effect severity was similar in the comparative trial with imipramine. 85 In fact, more patients withdrew from the study as a consequence of venlafaxine. ANTICONVULSANTS Gabapentin. Gabapentin is a popular first-line anticonvulsant used in treatment of neuropathic pain. 90 Gabapentin was developed as a structural GABA analogue, and recent in vivo studies demonstrated increased cerebral GABA concentrations within hours after administration of a single dose 43 and with longer-term administration in healthy subjects and patients with epilepsy. 43,70 Several other cellular mechanisms of action have been proposed, including competition with l-type amino acids for active transport, high-affinity binding to the 2 subunit of voltage-activated calcium channels, inhibition of voltage-activated sodium channels, increased serotonin concentrations, reduction in monoamine neurotransmitters, and prevention of neuronal death. 95 The primary mechanism responsible for gabapentin s analgesic effect remains uncertain. Several randomized, double-blinded, placebocontrolled studies of gabapentin use in painful peripheral neuropathy have been conducted (Table 3). Backonja et al. 3 studied 165 patients with painful diabetic neuropathy. Seventy of 84 patients (83%) receiving gabapentin and 65 of 81 (80%) receiving placebo completed the 8-week study. Gabapentin was titrated from 900 to 3600 mg/day over a period of 4 weeks or to the maximally tolerated dosage. The 8 Treatment of Painful Neuropathy MUSCLE & NERVE July 2004

Table 4. Randomized, placebo-controlled trials of lamotrigine.* Ref. no. Cause of neuropathy Daily dose (mg) n Design 53 Various 200 74 Parallel 8wk 83 HIV 300 29 Parallel 14 wk 21 DM 400 46 Parallel 8wk 82 HIV 400 600 92 ART; 135 Parallel non-art 11 wk Primary Result of primary on active drug (%) on placebo (%) VAS score P NS N/A N/A modified Gracely pain Numerical pain Gracely pain P 0.03 N/A N/A P 0.001 73 52 P 0.004 for ART patients; P NS for non-art patients 53 for ART patients 60 for non-art patients 39 Abbreviations: ART, antiretroviral therapy; DM, diabetes mellitus; N/A, not available; NS, non significant. *Main adverse events were rash (up to 25%), nausea (up to 11%), and infection (up to 11%). primary measure was daily pain severity as measured on an 11-point Likert. Mean daily pain scores were significantly lower in the gabapentin-treated group (P 0.001). 3 All secondary measures assessing sleep, mood, and quality of life also improved significantly in the gabapentin arm. Other randomized, double-blinded, placebo-controlled studies of gabapentin produced conflicting results. 67,79 Serpell et al. 79 enrolled patients with a variety of neuropathic pain syndromes, the majority being complex regional pain syndrome (28%); only 2% had diabetic neuropathy. Pain scores did not improve after 6 weeks. In a study of 18 patients with Guillain Barré syndrome admitted to an intensive care unit, there was a significant decrease in fentanyl requirements over a 7-day period in those receiving gabapentin as opposed to placebo. 67 Two studies, one open-label and the other a randomized, double-blinded crossover trial, compared gabapentin with tricyclics. 17,59 In the open-label study, 17 gabapentin was superior to amitryptiline in pain reduction (P 0.026), whereas the blinded trial found the two drugs to be equivalent in reducing pain. 59 A recent analysis of five randomized, placebocontrolled trials provides direction on gabapentin dosing for neuropathic pain. The conclusion was that gabapentin should be started at 300 mg on day 1, 600 mg on day 2, and 900 mg on day 3. Subsequent titration to 1800 mg/day was recommended to achieve greater efficacy, with doses up to 3600 mg/day needed in some patients. 4 However, doses as low as 900 mg/day were effective in a placebo-controlled, crossover study of painful diabetic neuropathy. 31 Gabapentin is usually well tolerated. Side effects include sedation, fatigue, dizziness, confusion, tremor, weight gain, peripheral edema, and headache. Contraindications and drug interactions are few. It is eliminated by renal excretion, and its clearance is reduced in patients with renal insufficiency, especially those with a creatinine clearance below 60 ml/min. 3 Cimetidine alters the renal excretion of gabapentin. Bioavailability is reduced by concomitant administration of magnesium or aluminumbased antacids. 101 Lamotrigine. Lamotrigine is a novel anticonvulsant that acts on voltage-sensitive sodium channels to stabilize neuronal membranes and inhibit neurotransmitter release, principally glutamate. 46 Several randomized, placebo-controlled, double-blinded studies of lamotrigine have been performed in various painful neuropathies (Table 4). Although there are some inconsistencies, most trials support its use in neuropathic pain management. An early placebocontrolled, double-blinded study of 100 patients with undefined causes of neuropathic pain failed to demonstrate an analgesic benefit at a dose of 200 mg/ day. 53 However, individual disease subgroups were not analyzed. Subsequent studies have evaluated the efficacy of lamotrigine in HIV-related 82,83 and diabetic neuropathy. 21 The first trial in painful HIV neuropathy enrolled 20 subjects in the placebo arm and only 9 on lamotrigine. 83 Patients receiving up to 300 mg/day of lamotrigine had a greater reduction in average pain compared with the placebo group (P 0.03). However, an overestimation of the treatment effect was possible, because 11 of 20 patients randomized to the active arm dropped out. Nearly half of the dropouts left the study because of skin Treatment of Painful Neuropathy MUSCLE & NERVE July 2004 9

Ref. no. Cause of neuropathy Table 5. Randomized, placebo-controlled trials of other anticonvulsants.* Daily dose (mg) n Design Primary Drug 74 DM Carbamazepine 200 600 30 Crossover 2wk 98 DM Carbamazepine 600 40 Crossover 1wk 76 DM Phenytoin 300 12 Crossover 23 wk 14 DM Phenytoin 300 40 Crossover 2wk 54 Various Phenytoin 15 mg/kg 20 Crossover 2wk 41 DM Sodium 1200 52 Parallel valproate 4wk Result of primary on active drug (%) on placebo (%) Subjective changes in pain intensity N/A 93 63 10-cm analogue P 0.05 70 23 Linear analogue P NS N/A N/A self-assessment Six-category P 0.02 74 26 0 10 linear VAS P 0.005 70 0 SF-MPQ P 0.05 N/A N/A Abbreviations: DM, diabetes mellitus; N/A, not available; NS, nonsignificant; SF-MPQ, short-form McGill pain questionnaire. *Main adverse events were somnolence (up to 53%), dizziness (up to 52%), gait changes (up to 42%), and nausea/vomiting (up to 40%). rash. This investigator group performed a larger HIV neuropathy trial in which patients were stratified according to whether they were using neurotoxic antiretroviral therapy (ART; didanosine, zalcitabine, or stavudine). 82 Lamotrigine was titrated to a dose of 400 mg/day, but a slower titration was used. The change in the Gracely pain slope for average pain indicated that lamotrigine was more effective in reducing pain in patients receiving neurotoxic ART (P 0.004) but was no more effective than placebo in patients not on these agents. The drug was well tolerated, with adverse events, including rash, being similar to placebo. No serious rash was reported, in contrast to the prior study, possibly because of the slower titration. In a diabetic neuropathy study, lamotrigine was beneficial at a daily dosage of 200 to 400 mg, and adverse events were not problematic using a slow titration. 21 Recommended lamotrigine dosing is 25 mg at night for 2 weeks, increasing weekly by 25 to 50 mg to a maximum dose of 400 mg/day. Side effects include mild to serious rash, including Stevens Johnson syndrome, dizziness, unsteadiness, drowsiness, and diplopia. 101 Rashes are more common in children and with rapid titration. Lamotrigine should be discontinued at the first sign of a drugrelated rash. If concomitantly used with valproic acid, titration should be even slower, beginning at 25 mg every other day, with maintenance dosing generally not exceeding 200 mg/day. Carbamazepine. Carbamazepine is an iminostilbene derivative chemically related to the tricyclic antidepressants. 2 It stabilizes membranes by inhibiting voltage-gated sodium channels. 57 Although it has been studied extensively in trigeminal neuralgia and is labeled for this indication, data regarding its effect in peripheral neuropathy are limited (Table 5). Two early double-blind crossover studies found carbamazepine to be effective in painful diabetic neuropathy at doses of 600 mg/day. 74,98 However, these are small studies, and each treatment phase lasted only 1 2 weeks, casting doubt on the results. Moreover, validated primary measures were not used. Adverse events were frequent, although they were minor and transient. They included somnolence, dizziness, nausea, vomiting, gait changes, and urticaria. Other side effects of carbamazepine include hyponatremia, leukopenia, thrombocytopenia, and hepatic dysfunction. 101 Oxcarbazepine is structurally similar to carbamazepine but has distinct pharmacokinetic and pharmacodynamic properties. 52 Like carbamazepine, oxcarbazepine slows the recovery rate of voltage-activated sodium channels, but it also inhibits high-threshold N- and P-type calcium channels and reduces glutamatergic transmission. As a result, it has the potential to modulate both peripheral and central neuropathic pain pathways. Whereas carbamazepine is metabolized via oxidation to 10-11-epoxide the metabolite responsible for most side effects oxcarbazepine undergoes reductive metabolism to a 10-monohydroxy derivative. 52 This reductive metabolism results in minimal involvement of hepatic cytochrome P-450 dependent enzymes, less autoinduction, and fewer drug interactions. As a result, oxcarbazepine boasts a safety advantage over carbamazepine. Unlike carbamazepine, ox- 10 Treatment of Painful Neuropathy MUSCLE & NERVE July 2004

Table 6. Randomized, placebo-controlled trials of analgesics.* Ref. no. Cause of neuropathy Drug Daily dose (mg) n Design Primary 31 DM Tramadol 210 (mean) 131 Parallel 6 wk 5-point Likert 84 Various Tramadol 200 400 34 Crossover 4 wk 10-point rating 29 DM Oxycodone 37 (mean) 159 Parallel 6 wk 11-point rating Result of primary on active drug (%) on placebo (%) P 0.001 68 36 P 0.001 32 9 P 0.002 N/A N/A Abbreviations: DM, diabetes mellitus; N/A, not available. *Main adverse events were tiredness (up to 56%), mouth dryness (up to 50%), constipation (up to 42%), dizziness (up to 44%), and nausea (up to 36%). carbazepine does not have a black box warning for aplastic anemia or agranulocytosis and is generally better tolerated. 68 Evidence is accumulating that oxcarbazepine is effective in treating neuropathic pain. Data from an open-label prospective study indicate that oxcarbazepine significantly improves pain scores in diabetic neuropathy patients. 11 Several trials to assess efficacy and define dosing are under way in Japan. Phenytoin. Phenytoin, like many other anticonvulsants, exerts its membrane-stabilizing effect by blocking sodium channels. 38 It is no longer a popular choice for neuropathic pain, because the few studies available are conflicting and adverse events are frequent. Furthermore, phenytoin inhibits insulin secretion, a potential problem in the diabetic population. 33 In a double-blind crossover study in patients with diabetic polyneuropathy, there was no significant benefit for phenytoin 300 mg/day over placebo (Table 5). 76 This is in contrast to the findings of Chadda et al. 14 of significant improvement in diabetic patients on the same dose. A single intravenous infusion of phenytoin at 15 mg/kg was shown to have an analgesic effect in acute flare-ups of neuropathic pain. The relief persisted beyond both the infusion time and plasma half-life of the drug. 54 Valproic Acid. Valproic acid was shown to increase GABA content in the brain and to prolong the repolarization phase of voltage-sensitive sodium channels. 38 There is only one randomized, controlled trial in painful peripheral neuropathy (Table 5). The study of 52 diabetic neuropathy patients demonstrated a significant improvement in pain in the valproate-treated group as compared with placebo at the end of 1 month. 41 Valproate was well tolerated at 1200 mg/day in divided doses; only one patient developed elevated liver enzymes. Other clinical trials are needed to reproduce these favorable results. TRAMADOL Tramadol, a centrally acting nonnarcotic analgesic medication with monoaminergic and opiate effects, has been used in Europe since the late 1970s and was first marketed in the United States in 1995. It has low-affinity binding to -opioid receptors coupled with mild inhibition of norepinephrine and serotonin reuptake. 71 Development of tolerance and dependence appear to be unusual events with tramadol. 72 Tramadol has been effective in blinded, placebo-controlled studies of painful diabetic neuropathy and other forms of painful neuropathy (Table 6). 33,84 Pain relief was manifest as early as 2 weeks, showing even greater effect by 4 weeks before a plateau was observed. 33 Overall health and social functioning improved significantly, although sleep indices did not. In a 6-month open-label extension that enrolled 120 patients from the randomized trial, tramadol was found to provide sustained relief of neuropathic pain. 34 Eighty-five patients completed the 6-month extension. By 30 days, average pain intensity scores for the former placebo patients were similar to those who had always received active drug. The frequency and severity of adverse events did not appear to increase with time. In a smaller placebocontrolled crossover study (Table 6), tramadol produced significant reductions in ratings for spontaneous and touch-evoked pain as well as dynamic allodynia by electronic toothbrush stimulation. 84 Although side effects from tramadol were frequent in this trial, they tended to be mild and did not correlate with the primary analgesic response. Treatment of Painful Neuropathy MUSCLE & NERVE July 2004 11

Tramadol dosing usually begins at 50 mg twice daily. The dose can be titrated upward at increments of 50 mg every 3 to 7 days, using a schedule in which medication is taken three of four times daily. The maximum recommended dose is 100 mg four times daily. Frequently reported side effects include constipation, headache, and nausea. Sedation and dizziness are less common, reported by less than 15% of patients, 33,34 suggesting that tramadol may be better tolerated than tricyclics in some individuals. Tramadol is contraindicated in patients with a previous hypersensitivity to opioid analgesics. It should be avoided in the setting of ongoing alcohol abuse, hypnotics, centrally acting analgesics, opioids, or psychotropic drugs. Increased risk of central nervous system depression or seizures has been described with concurrent use of other centrally acting drugs including neuroleptics and all major families of antidepressants. Other potential drug interactions include carbamazepine, digoxin, and warfarin. The abuse potential of tramadol appears to be low, but the agent is best avoided in patients with a prior history of addiction. 34 Because tramadol undergoes hepatic metabolism and is partially excreted unchanged in the urine, dosing should be reduced in patients with either hepatic (maximum dose of 50 mg twice daily) or renal insufficiency (maximum dose of 100 mg twice daily). OPIOID ANALGESICS Although the efficacy of opioids in neuropathic pain was disputed into the 1990s, 89 recent studies support an emerging role for opioid analgesics as a reasonable therapeutic alternative (Table 6). Prior to 2003, controlled data for opiates in neuropathic pain states was limited to postherpetic neuralgia. 97 Controlled-release oxycodone up to 60 mg/day was superior to placebo for steady and brief pain and allodynia in this crossover trial of 38 patients. Recently, controlled-release oxycodone demonstrated efficacy in painful diabetic neuropathy in a doubleblinded, placebo-controlled study. 29 Oxycodone dosing ranged between 10 and 99 mg/day. Significant improvement in all pain s and sleep quality was seen within 1 week of oxycodone therapy, excluding the worst pain category. The reduction in pain intensity occurred in the setting of relatively low average daily doses (37 mg), one third of the maximum allowed per study protocol. The median time to achieve mild pain (an average pain intensity rating of 4 on the 11-point ) was 6 days for oxycodone and 17 days for placebo. Measures for physical function and both general and mental health did not differ significantly between the two treatment arms, however. In a second randomized, double-blinded trial that included 81 patients with either refractory chronic peripheral or central neuropathic pain, reduction of pain intensity was significantly greater with high-strength (0.75 mg) than low-strength (0.15 mg) doses of levorphanol. 73 The degree of pain reduction was 36% in the high-strength group versus 21% in patients receiving the low-dose capsules. The level of pain reduction was not associated with prior opioid use. A major drawback of high-strength dosing was the greater degree of adverse events. Only patients receiving the high-dose tablets reported anger, irritability, mood or personality change, generalized weakness, confusion, and dizziness. The study withdrawal rate of 35% was also greater in the highstrength group. 73 Withdrawal rates between 20% and 25% are typical in opioid studies. 29,97 Not surprisingly, the frequency of adverse events is high in patients treated with opiate analgesics, ranging from 76% 97 to 96% 29 in these studies. Constipation, sedation, and nausea are most commonly reported. Neither opioid tolerance nor physical dependence was observed, 29 although longer-term studies have yet to be performed. Similar to tramadol, opioids should be used with extreme caution in patients with a history of addictive behavior. Patients should be counseled on the potential for drug tolerance and addiction, although such behavior has been uncommon in the experience of specialists using chronic opioids in this population. 25 Longeracting agents are preferred for chronic therapy, including extended-release oxycodone, morphine, and methadone. Dosing varies depending on the agent. In general, the dose should be slowly titrated upward until there is pain relief and improvement in function. Effective daily doses may be relatively low: 30 to 60 mg for extended-release oxycodone and 1 to 15 mg for methadone. Prophylactic laxative therapy should be considered when starting these agents. Opioids are contraindicated in patients with prior hypersensitivity, significant respiratory depression, obstructive pulmonary disease, and paralytic ileus. Opioids interact with central nervous system depressants; therefore, concomitant use should be avoided. MEXILETINE Trials of mexiletine, a class IB antiarrhythmic agent and oral analogue of lidocaine, have generated conflicting data in studies involving patients with dia- 12 Treatment of Painful Neuropathy MUSCLE & NERVE July 2004

Table 7. Randomized, placebo-controlled trials of mexiletine.* Ref. no. Cause of neuropathy Daily dose (mg) n Design 19 DM 10 mg/kg 16 Crossover 10 weeks 93 DM 450 675 95 Parallel 5 weeks 65 DM 225, 450, 126 Parallel 675 3 weeks 39 HIV 600 22 Crossover 6 weeks 40 HIV 600 126/145 Parallel 10 weeks Primary Result of primary on active drug (%) on placebo (%) FIS; VAS P 0.02 FIS, 94 VAS, 63 FIS, 13 VAS, 0 McGill VAS P NS N/A N/A score VAS score P 0.029 74 65 VAS score P 0.78 31 31 Gracely pain intensity P 0.38 46 48 Abbreviations; DM, diabetes mellitus; FIS, five-item symptom score ; N/A, not available; NS, nonsignificant. *Main adverse events were nausea (up to 29%) and vomiting (up to 24%). betic, 19,65,93 alcoholic, 61 and HIV-related 39,40 neuropathy (Table 7). In a crossover study of diabetic painful neuropathy in which mexiletine was titrated up to a daily dose of 10 mg/kg, the VAS score and clinical symptom showed significant improvement (P 0.02 and P 0.01, respectively) compared with placebo. 19 A larger study involving 126 diabetic patients also suggested improvement in sleep disturbances and nocturnal pain at 675 mg/ day. 65 In contrast, Stracke et al. 93 failed to differentiate between mexiletine and placebo in either the VAS or McGill pain s, although a subanalysis did suggest that stabbing or burning pain, heat sensations, and formication improved. Clinical trials that enrolled patients with HIV-related neuropathy failed to demonstrate any benefit for mexiletine at doses up to 600 mg/day. 39,40 The recommended starting dose is 150 mg/day, and this can be titrated up to 10 mg/kg per day divided into three daily doses. Main side effects include nausea, vomiting, dizziness, tremor, nervousness, headache, and liver function abnormalities (Table 7). Mexiletine is contraindicated in patients with second- or third-degree atrioventricular blockade or cardiogenic shock. 102 CAPSAICIN Capsaicin, an alkaloid extracted from chili peppers that depletes substance P from sensory nerves, has had a significant effect in most diabetic neuropathy trials but not in other painful neuropathies (Table 8). In diabetic neuropathy studies, the proportion of patients with improved pain control has ranged from 60% to 90%. 10,77,94 Ability to sleep, work, and perform other daily activities also improved significantly on capsaicin. 9,77 In a small open-label extension, at a mean follow-up of 22 weeks approximately 50% of patients had improved, 25% were unchanged, and 25% were worse. 94 However, more than half the 18 patients who entered the open-label study dropped out during the 48-week extension. Six of the dropouts left the study because of lack of relief. A major concern raised with regard to capsaicin trials is inadequate blinding from the burning sensation induced during early capsaicin application. The one study that used an active placebo as a control failed to demonstrate a significant effect for capsaicin. 47 However, only 18% of subjects in the study had diabetic neuropathy. Interestingly, another study found capsaicin to be no more effective than placebo in painful HIV-associated distal symmetrical peripheral neuropathy. 66 In fact, significantly higher pain scores were reported in the capsaicin group at the end of the first week of the 4-week trial. In contrast, in the Capsaicin Study Group trial the largest study that favored capsaicin over placebo treatment s were similar regardless of whether diabetic subjects developed burning sensations. 10 Capsaicin was equally effective as amitriptyline in reducing pain and improving daily activities in a double-blind randomized comparison study of 235 patients with diabetic neuropathy. 7 The systemic side effect profile favored capsaicin. Favorable response rates have been very high for vehicle placebos in capsaicin studies. In the Capsaicin Study Group trial, more than 50% of patients receiving placebo were believed to have improved on a physician global evaluation. 10 The patients reported a 45% mean percentage of pain relief. In the study that employed a placebo vehicle containing methyl nicotinate Treatment of Painful Neuropathy MUSCLE & NERVE July 2004 13

Ref. no. Table 8. Randomized, placebo-controlled trials of capsaicin cream (0.075% applied qid).* Cause of neuropathy n Design Primary 13 DM 46 Parallel 4 weeks 9 DM 252 Parallel 8 weeks 77 DM 49 Parallel 8 weeks 94 DM 20 Parallel 8 weeks Result of primary on active drug (%) on placebo (%) Pain severity P NS 71 50 Six step physician s global evaluation Six step physician s global evaluation Six step physician s global evaluation Verbal pain relief 47 Various 39 Parallel 8 weeks evaluation 66 HIV 20 Parallel Brief pain 4 weeks inventory Abbreviations: DM, diabetes mellitus; N/A, not available; NS, nonsignificant. *Main adverse events were burning (up to 73%), sneezing/coughing (up to 12%), and skin redness/rash (up to 10%). One leg received active drug; one leg, placebo. Methyl nicotinate used in initial placebo tube to induce stinging, erythema P 0.007 71 51 P 0.005 89 50 P 0.038 60 20 P NS 59 67 P NS N/A N/A to induce stinging and erythema, the percentage of limbs that improved at 12 weeks on a global was near 60% for both the active and placebo arms, even after a 4-week placebo wash-out phase. 47 Substance P is considered the primary neurotransmitter for polymodal nociceptive afferent fibers. In addition to substance-p depletion, capsaicin may cause epidermal nerve fiber degeneration, contributing to its analgesic effects. 63 Capsaicin 0.075% cream is available over the counter and should be applied to the painful region three to four times daily. It should be used in wellventilated areas, and patients should avoid rubbing their eyes after use. Nonsteroidal anti-inflammatory agents may be used if the initial burning from capsaicin is intense. This side effect is reported by a majority of patients but usually improves over several weeks as nociceptor membranes become desensitized and substance-p levels are depleted. 23,77,94 Other side effects include sneezing, coughing, rash, and skin irritation (Table 8). Capsaicin should not be used if there is known prior hypersensitivity to the cream or to hot chili peppers. There are no significant interactions with other medications. LEVODOPA There has been only one double-blind placebo-controlled study of levodopa in painful neuropathy. 22 The study enrolled 25 patients with diabetic peripheral neuropathy. Compared with placebo, VAS scores dropped significantly in the active arm by week 2, persisting through week 4 (P 0.004). The levodopa dosage used in the study was 100 mg/day three times a day. No adverse events were reported. DEXTROMETHORPHAN Dextromethorphan is a low-affinity NMDA glutamate receptor antagonist. A crossover study that enrolled 14 patients with diabetic neuropathy revealed a significant improvement in pain at a mean dose of dextromethorphan 381 mg/day compared with placebo (P 0.014). 60 Adverse events were frequent in the active arm, including sedation, dizziness, lightheadedness, and ataxia. Among patients in the trial, 16% dropped out because of sedation or ataxia. There were virtually no adverse events reported on placebo, suggesting that patients may have been unblinded to the treatment. 60 A recent parallel study of 19 patients that used lorazepam as a sedating placebo demonstrated a trend for dextromethorphan in reducing pain intensity, but this was not statistically significant. 75 In the responder subgroup, however, a dose-response effect on pain intensity was seen at higher doses. Sedation occurred in 71% of patients receiving dextromethorphan. 14 Treatment of Painful Neuropathy MUSCLE & NERVE July 2004

Table 9. Number-needed-to-treat analysis for 50% pain relief. Pharmacological class Neuropathic pain* Painful diabetic neuropathy Antidepressants, tricyclic antidepressants 2.6 (2.2 3.3) 3.0 (2.4 4.0) Balanced reuptake inhibitors, 2.0 (1.7 2.5) Noradrenergic reuptake inhibitors, 3.4 (2.3 6.6) Antidepressants, SSRIs 6.7 (3.4 435) 6.7 (3.4 435) Paroxetine, 2.9 Citalopram, 7.7 Venlafaxine 5.2 (2.7 5.9) Gabapentin 3.7 (2.4 8.3) 3.7 (2.4 8.3) Carbamazepine 3.3 (2.0 9.4) 3.3 (2.0 9.4) Phenytoin 2.1 (1.5 3.6) 2.1 (1.5 3.6) Tramadol 3.4 (2.3 6.4) 3.1 Oxycodone 2.5 (1.6 5.1) Capsaicin 5.9 (3.8 13) 5.9 (3.8 13) Mexiletine 10 (3.0 infinity) 10 (3.0 infinity) Levodopa 3.4 (1.5 infinity) 3.4 (1.5 infinity) Dextromethorphan 1.9 (1.1 3.7) 1.9 (1.1 3.7) Values in parentheses are 95% CI. *Composite analysis that combined studies with different causes of neuropathic pain. 90 From Ref. 89 From Ref. 85 From Ref. 97 Balanced reuptake inhibition of both serotonin and norepinephrine (amitriptyline, imipramine, colmipramine). Includes desipramine and maprotiline. NUMBER-NEEDED-TO-TREAT ANALYSES Increasing emphasis is being placed on the translation of evidence-based medicine into clinical practice. Along these lines, randomized placebocontrolled studies in neuropathic pain have been subjected to number-needed-to-treat analyses (NNT). 16 This methodology provides the clinician with a measure of efficacy that can be more readily translated into routine practice situations. The NNT refers to the number of subjects that need to be treated in order to achieve a defined clinical response in a single patient. In the context of pain studies, a 50% or greater reduction in the self-report of pain is considered clinically relevant and is used as the defined response. 90 For studies that do not specifically employ a 50% reduction as an measure, excellent/good/moderate pain relief or no/slight pain intensity grades may be categorized as satisfying this degree of pain reduction. 55 The NNT can be performed only on placebo-controlled studies, because a correction for placebo responders is included in the calculation. The formula is expressed as the reciprocal of the absolute risk reduction: NNT 1/ [response achieved active /total active ] [response achieved placebo /total placebo ]. 16 The 95% confidence interval (CI) for the NNT is obtained by taking the reciprocal value of the 95% CI for the absolute risk reduction. Although the NNT approach is only a coarse measure of a drug s effectiveness and does not account for study duration, it does inform on the rate and magnitude of the analgesic effect and allows for a reasonable comparison of different agents (Table 9). 15,57 Given the scarcity of head-to-head trials in neuropathic pain, the NNT can serve as a helpful guide in the choice of first- and second-line agents. Table 9 summarizes NNT data for various pharmacological agents. For studies of painful diabetic neuropathy, the NNT for 50% pain relief for amitriptyline was 2.1; paroxetine, 6.7; carbamazepine, 3.3; dextromethorphan, 1.9; and tramadol, 3.4. 62,90 Based on these findings, tricyclic antidepressants were recommended as firstline therapy for neuropathic pain. 90 Leading alternatives were gabapentin, carbamazepine, and tramadol. It should be noted that these recommendations preceded the publication of randomized, controlled trials of third-generation anticonvulsants and atypical antidepressants mentioned earlier. GENERAL TREATMENT GUIDELINES Pain management should begin with an effort to identify the etiology of the neuropathy, as directed therapy may help alleviate the symptoms. Prior to the initiation of any therapy, the physician and patient should discuss the goals and expectations of treatment. It is important that the patient have a realistic view of therapy and understand that re- Treatment of Painful Neuropathy MUSCLE & NERVE July 2004 15

Table 10. Pharmacological therapy for neuropathic pain in peripheral neuropathy. Medication Starting doses Maintenance doses and comments First line Gabapentin 100 300 mg tid Increase by 300 400-mg increments every 5 7 days to 3600 mg daily divided in 3 4 doses Tricyclic antidepressants 10 25 mg qhs Increase by 10 25 mg increments every 7 days to 100 150 mg qhs; titration can continue following blood levels (stay below 500 ng/ml) and electrocardiogram Tramadol 50 mg qd or bid Increase by 50-mg increments every 5 7 days to a maximum of 100 mg qid Second line Lamotrigine 25 mg qd or bid After 2 weeks, increase by 25-mg increments weekly to 100 200 mg bid Carbamazepine 100 200 mg qd or bid Increase by 100 200 mg every 7 days to 600 mg qd in divided doses; titration can continue following blood levels; Extended-release forms can be given on a bid schedule Bupropion SR 150 mg qd After 1 week, increase to 150 mg bid Venlafaxine XR 75 mg qd Increase by 75-mg increments every 7 days to 150 225 mg qd Opiate analgesics Varying doses: initiate with short-acting agent qid pm After 1 2 weeks, replace with longer-acting agent on a qd or bid schedule; careful titration is necessary. Topical Agents Capsaicin 0.075% Apply tid or qid Continue with starting dose; may be considered for first-line or adjunctive therapy sponses may vary from person to person and that pain relief is rarely complete. Some physicians find it helpful to have patients monitor their pain level using simple 5- or 10-point rating s that they can complete at home or in the clinic and bring to their appointment. Pharmacological agents should be initiated at low doses and titrated using small increments over several weeks until an adequate clinical response is observed or intolerable side effects appear. 25 Tolerance of agents with sedating profiles may be enhanced by starting the medication in a single bedtime dose. Slow titrations are especially important in elderly patients who receive other medications for chronic medical illness. Polypharmacy or multidimensional therapy may be considered when one drug provides partial relief but higher doses produce troublesome side effects. In this setting, a rational intervention would be to add a medication with a different mechanism of action or initiate a nonpharmacological approach. Two common reasons for treatment failure in the neuropathic pain population are stopping titrations before effective dosing levels are reached and immediate initiation of polypharmacy. 25 A drug trial of at least 4 to 6 weeks is recommended before switching to or adding another medication. Recommendations for first- and second-line pharmacological agents are provided in Table 10. The recommendations are based on the weight of evidence from randomized, controlled trials, taking adverse effect risks into account. Other considerations when choosing between the agents include cost, underlying medical illness, and potential drug interactions. Although many patients with neuropathic pain are treated simultaneously with two or more of the agents listed, systematic evaluations of combination therapy have not been performed. As mentioned earlier, whether some medication classes are more effective than others in treating certain qualities of neuropathic pain has not been addressed in convincing fashion. 89 The future of neuropathic pain management is promising. Pharmacological options continue to grow, and new agents are actively being investigated. An increasing number of FDA-approved indications are expected in the near future. Still, even current knowledge and available therapies appear underutilized. In a recent survey of 151 patients referred to a tertiary center, 25% had never received any of the conventional agents known to have efficacy in neuropathic pain. 28 Over 70% had never been prescribed anticonvulsants. Offering educational programs and raising awareness among health-care professionals are of critical importance if advances in neuropathic pain management are to reach this large group of patients. REFERENCES 1. Ascher JA, Cole JO, Colin JN, Feighner JP, Ferris RM, Fibiger HC, Golden RN, Martin P, Potter WZ, Richelson E. Bupropion: a review of its mechanism of antidepressant activity. J Clin Psychiatry 1995;56:395 401. 2. Backonja M. Use of anticonvulsants for treatment of neuropathic pain. Neurology 2002;59:S14 S17. 16 Treatment of Painful Neuropathy MUSCLE & NERVE July 2004

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